The hypothesis that the pancreatic beta cell is a primary site of pathology in human and experimental diabetes, and the knowledge that the beta cell population is affected by genetic background and response to immunologic injury has directed our attention to the need for further study of spontaneous models of Type I autoimmune diabetes. This request is for continued support of research projects designed to study the pathogenesis of diabetes in a unique model of insulin dependent diabetes, the Biobreeding/Worcester (BB/Wor) rat. Support is requested for breeding and related genetic experiments designed to characterize further the inbred lines of diabetes-prone (DP) and diabetes-resistant (DR) rats that are maintained at the University of Massachusetts Medical School. Support is requested for studies of the cellular mechanism of beta cell destruction in DP rats and the resistance to beta cell injury in DR rats. The role of environmental and specifically viral pathogens on spontaneous diabetes in DP rats and on induced and spontaneous diabetes in DR rats will be studied. The role of natural killer cells in the pathogenesis of beta cell destruction in DP and DR rats will also be studied with a recently described monoclonal antibody that specifically reacts with rat NK cells. The mechanism of diabetes in the BBZ/Wor rat, an animal model of both autoimmune beta cell destruction and obesity will also be studied. Virtually all of the proposed experiments are immunopathologic in nature. As such, all incorporate essential cellular immunology and morphologic readout systems, including routine light microscopy and immunocytochemistry as well as flow cytometry techniques for the identification of lymphocyte subsets.